Retroviruses have been postulated or established to play an etiologic role in many human lymphoid malignancies as well as in certain human autoimmune diseases. Despite this hypothesis, actual proof implicating human retroviruses in most of these diseases has remained elusive. Nevertheless, the recent isolation of two pathogenic retroviruses (HTLV I and II) from human T cell malignancies and the characterization of a third retrovirus (HIV) as the causative agent of acquired immunodeficiency disease (AIDS) has reawakened interest in this model. In particular, new data concerning the life cycle and growth of HIV have suggested new approaches to this problem. My laboratory has familiarized itself with these approaches by studying retroviral gene expression in several autoimmune mouse strains, and HIV. Now we are collecting human tissue with the goal of identifying new human pathogenic retroviruses. To date, we have assayed DNA and RNA from patient with juvenile rheumatoid arthritis, rheumatoid arthritis, and systemic lupus for evidence of pathogenic retroviruses. We found that they do not contain sequences capable of cross-hybridizing with probes derived from HTLVI or HIV. In addition, the RNA did not contain one form of human endogenous retrovirus at elevated levels. While these studies probably rule out these, or closely related retroviruses, as causing these diseases, they do not invalidate the general model. Each new type of human pathogenic retrovirus has been distinctly different from previous isolates. The discovery of a pathogenic retrovirus in any of these diseases would be a dramatic breakthrough in understanding its etiology, and might establish a mechanism of preventing that disease through vaccination.